Metastatic melanoma has a dismal prognosis, with 10-year survival rates of < 10%. A major underlying reason for this is that no systemic treatment provides durable benefit due to development of resistance to current therapies. A new potential strategy for treating melanoma is proposed that exploits differences in oxidative metabolism between cancerous and non-malignant cells to selectively kill melanoma cells. This new mitochondrial-targeted intervention utilizes a class of small molecules, based on triphenylphosphonium (TPP), to selectively increase superoxide levels and oxidative stress-induced melanoma cell killing, relative to normal cells. Our preliminary data demonstrate that TPP-based compounds can be designed to selectively kill melanoma cells relative to normal melanocytes. We further show that TPP-based compounds can be designed to promote melanoma cell death via increased oxidative stress and that the effect can be enhanced with inhibitors of hydroperoxide metabolism. In addition, orally-administered 10-TPP significantly suppressed melanoma tumor growth in mice, with no measurable toxicity. This research is innovative because no other therapy targets differences in mitochondrial oxidative metabolism in melanoma cells vs normal cells to selectively kill melanoma cells. This research is significant because the success of these aims can result in a new treatment paradigm for metastatic melanoma that can potentially provide durable benefit to patients. The central hypothesis is that TPP-based therapies can be developed to selectively kill melanoma cells relative to non-malignant cells by exploiting differences in oxidative metabolism of melanoma cells relative to non-malignant cells. This hypothesis will be tested in three Specific Aims: SA1: Identify TPP structure activity relationships (SAR) and mechanisms that selectively promote cell death and increase oxidative stress in melanoma cells, relative to non-malignant melanocytes. SA2: Determine the potential for TPP based drugs to selectively enhance melanoma cell killing when combined with standard clinically relevant chemotherapeutic agents and/or inhibitors of hydroperoxide metabolism. SA3: Identify TPP SAR as well as routes of administration that could result in the development of effective combined-modality therapies for human melanomas in xenograft models. Successful completion of these studies will identify key design traits of TPP-drugs that selectively promote melanoma cell death vs. normal melanocytes, as well as establish a detailed mechanistic understanding of TPP-based combination therapies that can ultimately lead to well-tolerated protocols for treating metastatic melanoma that can be advanced to human clinical trials.